Niraparib Synthesis via Condensation and Segmentation
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Solution Overview
Problem
Despite advances in ovarian cancer treatment, patients with germline BRCA1 or BRCA2 mutations often experience relapse, and those without these mutations may have limited responses to treatments, highlighting the need for effective PARP inhibitor therapies.
Innovation Solution
A process for preparing niraparib, a potent PARP inhibitor, involving specific chemical reactions and catalysts to produce pharmaceutically acceptable salts, which are useful in treating ovarian cancer, particularly in patients with BRCA1 or BRCA2 mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If conventional treatment methods are used for ovarian cancer, then initial treatment response may be achieved, but patients eventually relapse and subsequent responses are limited in duration
Solution Approach 1:
The patent employs parameter changes by utilizing PARP inhibition to alter the biological activity parameters of cancer cells with DNA repair defects. By targeting the PARP enzyme pathway, the treatment changes the cellular repair mechanism parameters, leading to sustained treatment response and reduced relapse in patients with BRCA1/2 mutations or platinum-sensitive ovarian cancer.
2Reliability
If PARP inhibitor therapy is administered, then treatment efficacy is improved for BRCA1/2 mutation carriers, but the process requires precise chemical synthesis to ensure drug quality
Solution Approach 1:
The patent applies segmentation by dividing the complex synthesis of niraparib into multiple discrete steps, each producing a specific intermediate compound. The process segments the molecular construction into manageable stages: starting from 2-nitro-3-(pyrrolidin-1-yl)benzalmalononitrile, proceeding through various cyclization and substitution reactions to form the final pyrrolo[2,4-b]pyridine core structure with precise stereochemistry.
Solution Approach 2:
The patent employs preliminary action by pre-synthesizing and characterizing intermediate compounds before final assembly. Each intermediate is purified and characterized to ensure quality control before proceeding to the next synthesis step, preventing error propagation and ensuring manufacturing precision in the final drug product.
3Manufacturing precision
If complex chemical synthesis processes are used to produce niraparib, then drug purity is achieved, but manufacturing complexity and time increase
Solution Approach 1:
The patent applies continuity of useful action by designing a synthesis pathway where each reaction step directly builds toward the final product without unnecessary intermediate isolations or purifications. The continuous optimization of reaction conditions and workup procedures maintains product purity while reducing process complexity and manufacturing time.
4Reliability
If multiple synthesis steps are employed to produce pharmaceutically acceptable salts of niraparib, then product quality is ensured, but production time and resource consumption increase
Solution Approach 1:
The patent applies discarding and recovering by efficiently managing byproducts and solvents from each synthesis step. Recovery procedures are optimized to reuse materials where possible, and waste streams are minimized through careful selection of reagents and reaction conditions, reducing both time and resource consumption while maintaining product quality.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process enables the production of niraparib, enhancing treatment options for ovarian cancer patients by targeting PARP pathways, offering clinical benefits for both mutation carriers and non-carriers with platinum-sensitive high-grade serous ovarian cancer.
Implementation Method 1
contacting a compound of Formula (2) with a compound of Formula (3) wherein the contacting results in formation of a water molecule
Implementation Method 2
the contacting is in presence of an acid. In some embodiments, the acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid, trifluoromethanesulfonic acid, aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethane sulfonic acid (ESA), or any combination thereof
Data Source
AI summary
Disclosed herein are methods and processes of preparing niraparib and pharmaceutically acceptable salts thereof, and intermediates and their salts useful for the synthesis of niraparib.